Haico van Attikum

Keywords CHK2 CHEK2 DNA damage repair tumor suppressor deep mutational scanning variant effect mapping yeast Saccharomyces cerevisiae breast cancer Introduction DNA lesions activate cell-cycle checkpoints, which are important for maintaining genome integrity.1,2,3 CHEK2 (MIM: 604373), a tumor suppressor gene encoding the serine/threonine checkpoint kinase 2 (CHK2), is an important checkpoint regulator of DNA repair, cell-cycle regulation, and apoptosis in response to DNA damage.4 Germline...

Highlights Functional assays have been developed that can determine the impact of missense variants of uncertain significance (VUS) on CHK2 protein function. Functional analyses of CHEK2 missense VUS reveal an association between impaired protein function and increased breast cancer risk. Damaging CHEK2 missense VUS may be associated with a risk of breast cancer similar to that of protein-truncating variants.

Highlights Homologous recombination (HR)-deficient tumors are hypersensitive to poly-(ADP)-ribose polymerase inhibitors (PARPi)-induced DNA damage. Therefore, PARPi have shown great promise in the clinic, but rates of pre-existing and acquired resistance are high.